Aims: The aim of this research is to examine genetic factors that influence the risk of lung cancer and to consider interactions with environmental factors. To this end, I continue to examine the role of genetic susceptibility in the etiology of lung cancer in two studies. The first is a case-control study of African-Americans and Caucasians in Los Angeles County. Subject enrollment (356 cases and 731 control subjects) was completed by S. London while she was a faculty member at the University of Southern California. During the past year, we have examined polymorphisms in several DNA repair genes - XPD, XRCC1 and XRCC3. I am also participating in an international collaborative project to pool original data from studies of genetic polymorphisms and lung cancer risk to improve power to examine gene-environment interactions. The other study is an NCI-funded cohort of 18,244 Shanghai men. This is one of the few cohort studies with prospectively collected blood and urine samples and an adequate proportion of smokers to yield sufficient lung cancer cases. We have been conducting nested case-control studies of 259 incident lung cancers and matched controls. The DNA source is from serum which presents challenges because of the smaller quantity of the genetic material compared to whole blood. In the past year we have examined the relation between a urinary biomarker of dietary intake of isothiocyanates and polymorphisms in glutathione S-transferase genes that are involved in their excretion. The Shanghai cohort offers a unique opportunity to examine this gene-diet interaction because of the high intake of vegetable sources of isothiocyanates. The prospectively collected urine samples enable assessment of isothiocyanates unbiased by effects of the disease process. We have also examined the relation between lung cancer risk and CYP1A1 polymorphisms. We are currently analyzing data on lung cancer risk in relation to prediagnostic serum levels of insulin-like growth factor-1 and its major binding protein IGFBP-3. These samples were analyzed at NIEHS in collaboration with Dr. Greg Travlos after extensive laboratory comparision of assay methods. Because levels may be altered by the disease process or treatment, results from prospective analyses are needed to evaluate the association. Procedures and techniques: The case-control study in Los Angeles uses standard case-control methodology. Population controls were enrolled from driver's licence and Medicare lists. The Shanghai study analyses use nested case control studies of incident lung cancer within the prospective cohort. Genotyping is done by PCR based methods. Accomplishments: A number of publications have emerged from the study of genetic polymorphisms and lung cancer risk in African-Americans and Caucasians - 18 to date. In the past year, we have had two manuscripts accepted on DNA repair polymorphisms and lung cancer risk. In the Shanghai cohort study, we have published evidence of a gene-diet interaction between isothiocyanate intake and genetic polymorphisms of GSTM1 and GSTT1 that are involved in their metabolism. Our analysis of IGF-1 and IGF1-BP3 in this cohort represents the first prospective look at this association.